Obesity afflicts millions of people, and is a major risk factor for Type II diabetes and morbidity. The melanocortin pathway has been clearly identified in mice and humans to be involved in the regulation of satiety, obesity, and energy homeostasis. The goal of this research project is characterize the human melanocortin-4 receptor (MC4R) N- terminal 1-26 domain peptide agonist, identify how it molecularly interacts with the MC4R to mechanistically function as a full agonist. These data will be used to generate novel and potent MC4R agonist molecules as molecular probes and potential central nervous system (CNS) drugs. The impact of the anticipated results on the medicinal chemistry and obesity research fields could challenge the existing paradigms for ligand design strategies for melanocortin receptor based therapeutics, GPCR based therapeutics, as well as provide novel tools to probe weight and energy homeostasis.